tbuckley/cabot-search huggingface dataset:
SrCuSi<sub>4</sub>O<sub>10</sub>/GelMA Composite Hydrogel‐Mediated Vital Pulp Therapy: Integrating Antibacterial Property and Enhanced Pulp Regeneration Activity
Authors: Yu Qiu, Jun Tian, Siyi Kong, Yanping Feng, Yangyu Lu, Lefeng Su, Yanling Cai, Mengjie Li, Jiang Chang, Chen Yang, Xi Wei
Journal: Advanced Healthcare Materials (2023)

Abstract Vital pulp therapy (VPT) is considered a conservative treatment for preserving pulp viability in caries‐induced dental pulp infections. However, bacterial contamination negatively affects dentine‐pulp complex repair. The common capping materials show limited antimicrobial effects against some microorganisms. To improve the VPT efficacy, capping materials with increased antibacterial properties and enhanced odontogenic and angiogenic activities are needed. Herein, a SrCuSi 4 O 10 /gelatin methacrylate(SC/Gel) composite hydrogel has been proposed for infected dental pulp treatment. SrCuSi 4 O 10 (SC) is a microscale bioceramic composed of assembled multilayered nanosheets that possesses good near‐infrared photothermal conversion ability and multiple bioactivities due to sustained Sr 2+ , Cu 2+ , and SiO 3 2− ion release. It is shown that the SC/Gel composite hydrogel efficiently eliminates Streptococcus mutans and Lactobacillus casei and inhibits biofilm formation under photothermal heating, while the ion extract from SC promotes odontogenesis of rat dental pulp stem cells and angiogenesis of human umbilical vein endothelial cells. The as‐designed therapeutic effect of SC/Gel composite hydrogel‐mediated VPT has been proven in a rat dental pulp infection model and yielded improved dentine‐pulp complex repair compared with the commercially used iRoot® BP Plus. This study suggests that the SC/Gel composite hydrogel is a potential pulp‐capping material with improved effects on dentine−pulp complex repair in infected pulp.
Authors' Reply: Urine Metabolomic Versus Standard Chemistry Analysis: What can Metabolomic Analysis Bring to the Treatment and Prevention of Urolithiasis?
Authors: Charat Thongprayoon, John C. Lieske, Andrew D. Rule, Aleksandar Denic
Journal: Journal of the American Society of Nephrology (2023)

Thongprayoon, Charat; Lieske, John C.; Rule, Andrew D.; Denic, Aleksandar Author Information
An Open-label Phase I Study of GDC-0927 in Postmenopausal Women with Locally Advanced or Metastatic Estrogen Receptor–Positive Breast Cancer
Authors: Sarat Chandarlapaty, Maura N. Dickler, Jose Alejandro Perez Fidalgo, Rafael Villanueva-Vázquez, Jennifer Giltnane, Mary Gates, Ching-Wei Chang, Sravanthi Cheeti, Jill Fredrickson, Xiaojing Wang, Ann Collier, Heather M. Moore, Ciara Metcalfe, Jennifer Lauchle, Eric W. Humke, Aditya Bardia
Journal: Clinical Cancer Research (2023)

Abstract Purpose: GDC-0927 is a novel, potent, nonsteroidal, orally bioavailable, selective estrogen receptor (ER) degrader that induces tumor regression in ER+ breast cancer xenograft models. Patients and Methods: This phase I dose-escalation multicenter study enrolled postmenopausal women with ER+/HER2− metastatic breast cancer to determine the safety, pharmacokinetics, and recommended phase II dose of GDC-0927. Pharmacodynamics was assessed with [18F]-fluoroestradiol (FES) PET scans. Results: Forty-two patients received GDC-0927 once daily. The MTD was not reached. The most common adverse events (AE) regardless of causality were nausea, constipation, diarrhea, arthralgia, fatigue, hot flush, back pain, and vomiting. There were no deaths, grade 4/5 AEs, or treatment-related serious AEs. Two patients experienced grade 2 AEs of special interest of deep vein thrombosis and jugular vein thrombosis, both considered unrelated to GDC-0927. Following dosing, approximately 1.6-fold accumulation was observed, consistent with the observed half-life and dosing frequency. There were no complete or partial responses. Pharmacodynamics was supported by &amp;gt;90% reduction in FES uptake and an approximately 40% reduction in ER expression, suggesting ER degradation is not the mechanistic driver of ER antagonism. Twelve patients (29%) achieved clinical benefit; 17 patients (41%) showed a confirmed best overall response of stable disease. Baseline levels of ER and progesterone receptor protein and mutant ESR1 circulating tumor DNA did not correlate with clinical benefit. Conclusions: GDC-0927 appeared to be well tolerated with pharmacokinetics supporting once-daily dosing. There was evidence of target engagement and preliminary evidence of antitumor activity in heavily pretreated patients with advanced/metastatic ER+/HER2− breast cancer with and without ESR1 mutations.
Global, Race-Neutral Reference Equations and Pulmonary Function Test Interpretation
Authors: Alexander T. Moffett, Cole Bowerman, Sanja Stanojevic, Nwamaka D. Eneanya, Scott D. Halpern, Gary E. Weissman
Journal: JAMA Network Open (2023)

Importance Race and ethnicity are routinely used to inform pulmonary function test (PFT) interpretation. However, there is no biological justification for such use, and it may reinforce health disparities. Objective To compare the PFT interpretations produced with race-neutral and race-specific equations. Design, Setting, and Participants In this cross-sectional study, race-neutral reference equations recently developed by the Global Lung Function Initiative (GLI) were used to interpret PFTs performed at an academic medical center between January 2010 and December 2020. The interpretations produced with these race-neutral reference equations were compared with those produced using the race and ethnicity–specific reference equations produced by GLI in 2012. The analysis was conducted from April to October 2022. Main Outcomes and Measures The primary outcomes were differences in the percentage of obstructive, restrictive, mixed, and nonspecific lung function impairments identified using the 2 sets of reference equations. Secondary outcomes were differences in severity of these impairments. Results PFTs were interpreted from 2722 Black (686 men [25.4%]; mean [SD] age, 51.8 [13.9] years) and 5709 White (2654 men [46.5%]; mean [SD] age, 56.4 [14.3] years) individuals. Among Black individuals, replacing the race-specific reference equations with the race-neutral reference equations was associated with an increase in the prevalence of restriction from 26.8% (95% CI, 25.2%-28.5%) to 37.5% (95% CI, 35.7%-39.3%) and of a nonspecific pattern of impairment from 3.2% (95% CI, 2.5%- 3.8%) to 6.5% (95% CI, 5.6%-7.4%) and no significant change in the prevalence of obstruction (19.9% [95% CI, 18.4%-21.4%] vs 19.5% [95% CI, 18.0%-21.0%]). Among White individuals, replacing the race-specific reference equations with the race-neutral reference equations was associated with a decrease in the prevalence of restriction from 22.6% (95% CI, 21.5%-23.6%) to 18.0% (95% CI, 17.0%-19.0%), a decrease in the prevalence of a nonspecific pattern of impairment from 8.7% (95% CI, 7.9%-9.4%) to 4.0% (95% CI, 3.5%-4.5%), and no significant change in the percentage with obstruction from 23.9% (95% CI, 22.8%-25.1%) to 25.1% (95% CI, 23.9%- 26.2%). The race-neutral reference equations were associated with an increase in severity in 22.8% (95% CI, 21.2%-24.4%) of Black individuals and a decrease in severity in 19.3% (95% CI, 18.2%-20.3%) of White individuals vs the race-specific reference equations. Conclusions and Relevance In this cross-sectional study, the use of race-neutral reference equations to interpret PFTs resulted in a significant increase in the number of Black individuals with respiratory impairments along with a significant increase in the severity of the identified impairments. More work is needed to quantify the effect these reference equations would have on diagnosis, referral, and treatment patterns.
What is Frailty?
Authors: Lisa Jane Brighton, Suzanne Lareau, Matthew Maddocks, Christian Osadnik, Lies Lahousse, Annemarie Lee, Jennifer Allison, Jonathan Singer, Dmitry Rozenberg, William DC Man, Lauren Ferrante, Martijn A Spruit, Chris Burtin, Samantha L Harrison, Anand S Iyer
Journal: American Journal of Respiratory and Critical Care Medicine (2023)
Questions in Mild Asthma: An Official American Thoracic Society Research Statement
Authors: Arjun Mohan, Njira L. Lugogo, Nicola A. Hanania, Helen K. Reddel, Praveen Akuthota, Paul M. O’Byrne, Theresa Guilbert, Alberto Papi, David Price, Christine R. Jenkins, Monica Kraft, Leonard B. Bacharier, Louis-Phillippe Boulet, Barbara P. Yawn, Roy Pleasants, Stephen C. Lazarus, Richard Beasley, Gail Gauvreau, Elliot Israel, Elena K. Schneider-Futschik, Arzu Yorgancioglu, Fernando Martinez, Wendy Moore, Kaharu Sumino
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

Section:ChooseTop of pageAbstract <<OverviewIntroductionMethodsDefinition of Mild AsthmaPathophysiology of Mild A...Management of Mild AsthmaPediatric Research Needs ...Patient Perspective on Mi...ConclusionsReferences
Tracer metabolomics reveals the role of aldose reductase in glycosylation
Authors: Silvia Radenkovic, Anna N. Ligezka, Sneha S. Mokashi, Karen Driesen, Lynn Dukes-Rimsky, Graeme Preston, Luckio F. Owuocha, Leila Sabbagh, Jehan Mousa, Christina Lam, Andrew Edmondson, Austin Larson, Matthew Schultz, Pieter Vermeersch, David Cassiman, Peter Witters, Lesa J. Beamer, Tamas Kozicz, Heather Flanagan-Steet, Bart Ghesquière, Eva Morava
Journal: Cell Reports Medicine (2023)

Abnormal polyol metabolism is predominantly associated with diabetes, where excess glucose is converted to sorbitol by aldose reductase (AR). Recently, abnormal polyol metabolism has been implicated in phosphomannomutase 2 congenital disorder of glycosylation (PMM2-CDG) and an AR inhibitor, epalrestat, proposed as a potential therapy. Considering that the PMM2 enzyme is not directly involved in polyol metabolism, the increased polyol production and epalrestat's therapeutic mechanism in PMM2-CDG remained elusive. PMM2-CDG, caused by PMM2 deficiency, presents with depleted GDP-mannose and abnormal glycosylation. Here, we show that, apart from glycosylation abnormalities, PMM2 deficiency affects intracellular glucose flux, resulting in polyol increase. Targeting AR with epalrestat decreases polyols and increases GDP-mannose both in patient-derived fibroblasts and in pmm2 mutant zebrafish. Using tracer studies, we demonstrate that AR inhibition diverts glucose flux away from polyol production toward the synthesis of sugar nucleotides, and ultimately glycosylation. Finally, PMM2-CDG individuals treated with epalrestat show a clinical and biochemical improvement.
Trends in Opioid Misuse Among Individuals Aged 12 to 21 Years in the US
Authors: Lauren Klein Warren, Joella Adams, Georgiy Bobashev
Journal: JAMA Network Open (2023)

Although opioid misuse has been decreasing among US youths and adolescents in recent years, it is unclear what has contributed to this trend and how this trend differs by age group and sex over time.To identify trends in opioid misuse among youths and young adults across and between ages, birth cohorts, and sexes.Cross-sectional National Survey on Drug Use and Health (NSDUH) public-use files were used to produce nationally representative pseudocohorts. The survey population includes the civilian US population in the 50 states and Washington, DC. Individuals without a fixed address and institutionalized individuals were excluded. Respondents to the NSDUH are a population-based sample selected using a stratified cluster design. For the years (January 1, 2002, to December 31, 2019) and ages (12-21 years) analyzed, the sample sizes ranged from 1607 to 3239 respondents. Data were analyzed from January 1, 2022, to April 12, 2023, for the main outcome by age, sex, and pseudocohort.Respondents were asked whether they misused prescription opioids or used heroin in the past year. The analysis hypotheses were formulated and tested after data collection.In a total of 5 pseudocohorts, data from 114 412 respondents aged 12 to 21 years were analyzed; the unweighted distribution of male sex (complement was female) ranged from 47.7% to 52.6% (mean [SD], 50.6% [1.1%]). Response rates ranged from 45.8% to 71.3%. High school-aged youths and young adults had distinctly lower rates of opioid misuse in later pseudocohorts compared with earlier ones. Rates of misuse among individuals aged 16 years were 2.80% (95% CI, 1.06%-4.54%) higher in 2002 vs 2008; among those aged 18 years, rates were 4.36% (95% CI, 1.85%-6.87%) higher in 2002. Similarly, rates of misuse among individuals aged 16 years were 3.93% (95% CI, 2.15%-5.71%) higher in 2008 vs 2014; among those aged 17 years, rates were 3.41% (95% CI, 1.94%-4.88%) higher in 2008. Similar patterns were observed by sex. In earlier cohorts, younger female participants had higher rates of opioid misuse than their male counterparts and older male participants had higher rates than their female counterparts. Sex differences decreased in later cohorts.The findings of this cross-sectional study of US youths and young adults suggest that high school-aged individuals consistently misused fewer opioids in later pseudocohorts overall and by sex. Sex differences in opioid rates also diminished in later pseudocohorts. A decrease in drug availability and general exposure to the harms of opioid use could be contributing to these findings. Future planned research using this pseudocohort approach will examine polysubstance use and evaluate how substance use differs by other sociodemographic characteristics.
Neutrophil extracellular traps and extracellular histones potentiate IL-17 inflammation in periodontitis
Authors: Tae Sung Kim, Lakmali M. Silva, Vasileios Ionas Theofilou, Teresa Greenwell-Wild, Lu Li, Drake Winslow Williams, Tomoko Ikeuchi, Laurie Brenchley, Thomas H. Bugge, Patricia I. Diaz, Mariana J. Kaplan, Carmelo Carmona-Rivera, Niki M. Moutsopoulos
Journal: The Journal of Experimental Medicine (2023)

Neutrophil infiltration is a hallmark of periodontitis, a prevalent oral inflammatory condition in which Th17-driven mucosal inflammation leads to destruction of tooth-supporting bone. Herein, we document that neutrophil extracellular traps (NETs) are early triggers of pathogenic inflammation in periodontitis. In an established animal model, we demonstrate that neutrophils infiltrate the gingival oral mucosa at early time points after disease induction and expel NETs to trigger mucosal inflammation and bone destruction in vivo. Investigating mechanisms by which NETs drive inflammatory bone loss, we find that extracellular histones, a major component of NETs, trigger upregulation of IL-17/Th17 responses, and bone destruction. Importantly, human findings corroborate our experimental work. We document significantly increased levels of NET complexes and extracellular histones bearing classic NET-associated posttranslational modifications, in blood and local lesions of severe periodontitis patients, in the absence of confounding disease. Our findings suggest a feed-forward loop in which NETs trigger IL-17 immunity to promote immunopathology in a prevalent human inflammatory disease.
PROTACs: A novel strategy for cancer drug discovery and development
Authors: Xin Han, Yi Sun
Journal: MedComm (2023)

Proteolysis targeting chimera (PROTAC) technology has become a powerful strategy in drug discovery, especially for undruggable targets/proteins. A typical PROTAC degrader consists of three components: a small molecule that binds to a target protein, an E3 ligase ligand (consisting of an E3 ligase and its small molecule recruiter), and a chemical linker that hooks first two components together. In the past 20 years, we have witnessed advancement of multiple PROTAC degraders into the clinical trials for anticancer therapies. However, one of the major challenges of PROTAC technology is that only very limited number of E3 ligase recruiters are currently available as E3 ligand for targeted protein degradation (TPD), although human genome encodes more than 600 E3 ligases. Thus, there is an urgent need to identify additional effective E3 ligase recruiters for TPD applications. In this review, we summarized the existing RING-type E3 ubiquitin ligase and their small molecule recruiters that act as effective E3 ligands of PROTAC degraders and their application in anticancer drug discovery. We believe that this review could serve as a reference in future development of efficient E3 ligands of PROTAC technology for cancer drug discovery and development.
A Specific Target BP in Chronic Kidney Disease Remains Unclear
Authors: Takayuki Yamada, Chethan M. Puttarajappa, Csaba P. Kovesdy, Yoshitsugu Obi
Journal: Journal of the American Society of Nephrology (2023)

Yamada, Takayuki; Puttarajappa, Chethan M.; Kovesdy, Csaba P.; Obi, Yoshitsugu Author Information
Severe and fatal neonatal infections linked to a new variant of echovirus 11, France, July 2022 to April 2023
Authors: Mathilde Grapin, Audrey Mirand, Didier Pinquier, Aurélie Basset, Matthieu Bendavid, Maxime Bisseux, Marion Jeannoël, Bérengère Kireche, Manoelle Kossorotoff, Anne-Sophie L’Honneur, Lila Robin, Yves Ville, Sylvain Renolleau, Véronique Lemee, Pierre-Henri Jarreau, Isabelle Desguerre, Florence Lacaille, Marianne Leruez-Ville, Clémence Guillaume, Cécile Henquell, Alexandre Lapillonne, Isabelle Schuffenecker, Mélodie Aubart
Journal: Eurosurveillance (2023)

We report nine severe neonatal infections caused by a new variant of echovirus 11. All were male, eight were twins. At illness onset, they were 3–5 days-old and had severe sepsis and liver failure. This new variant, detected in France since April 2022, is still circulating and has caused more fatal neonatal enterovirus infections in 2022 and 2023 (8/496; 1.6%, seven associated with echovirus 11) compared with 2016 to 2021 (7/1,774; 0.4%). National and international alerts are warranted.
Smart Thermometer–Based Participatory Surveillance to Discern the Role of Children in Household Viral Transmission During the COVID-19 Pandemic
Authors: Yi-Ju Tseng, Karen L. Olson, Danielle Bloch, Kenneth D. Mandl
Journal: JAMA Network Open (2023)

Importance Children’s role in spreading virus during the COVID-19 pandemic is yet to be elucidated, and measuring household transmission traditionally requires contact tracing. Objective To discern children’s role in household viral transmission during the pandemic when enveloped viruses were at historic lows and the predominance of viral illnesses were attributed to COVID-19. Design, Setting, and Participants This cohort study of a voluntary US cohort tracked data from participatory surveillance using commercially available thermometers with a companion smartphone app from October 2019 to October 2022. Eligible participants were individuals with temperature measurements in households with multiple members between October 2019 and October 2022 who opted into data sharing. Main Outcomes and Measures Proportion of household transmissions with a pediatric index case and changes in transmissions during school breaks were assessed using app and thermometer data. Results A total of 862 577 individuals from 320 073 households with multiple participants (462 000 female [53.6%] and 463 368 adults [53.7%]) were included. The number of febrile episodes forecast new COVID-19 cases. Within-household transmission was inferred in 54 506 (15.4%) febrile episodes and increased from the fourth pandemic period, March to July 2021 (3263 of 32 294 [10.1%]) to the Omicron BA.1/BA.2 wave (16 516 of 94 316 [17.5%]; P &amp;amp;lt; .001). Among 38 787 transmissions in 166 170 households with adults and children, a median (IQR) 70.4% (61.4%-77.6%) had a pediatric index case; proportions fluctuated weekly from 36.9% to 84.6%. A pediatric index case was 0.6 to 0.8 times less frequent during typical school breaks. The winter break decrease was from 68.4% (95% CI, 57.1%-77.8%) to 41.7% (95% CI, 34.3%-49.5%) at the end of 2020 ( P &amp;amp;lt; .001). At the beginning of 2022, it dropped from 80.3% (95% CI, 75.1%-84.6%) to 54.5% (95% CI, 51.3%-57.7%) ( P &amp;amp;lt; .001). During summer breaks, rates dropped from 81.4% (95% CI, 74.0%-87.1%) to 62.5% (95% CI, 56.3%-68.3%) by August 2021 ( P = .02) and from 83.8% (95% CI, 79.2%-87.5) to 62.8% (95% CI, 57.1%-68.1%) by July 2022 ( P &amp;amp;lt; .001). These patterns persisted over 2 school years. Conclusions and Relevance In this cohort study using participatory surveillance to measure within-household transmission at a national scale, we discerned an important role for children in the spread of viral infection within households during the COVID-19 pandemic, heightened when schools were in session, supporting a role for school attendance in COVID-19 spread.
Weekly Adaptive Radiotherapy vs Standard Intensity-Modulated Radiotherapy for Improving Salivary Function in Patients With Head and Neck Cancer
Authors: Joël Castelli, Juliette Thariat, Karen Benezery, Ali Hasbini, Bernard Gery, Antoine Berger, Xavier Liem, Sébastien Guihard, Sophie Chapet, Sébastien Thureau, Pierre Auberdiac, Pascal Pommier, Amandine Ruffier, Lionel Perrier, Anne Devillers, Boris Campillo-Gimenez, Renaud de Crevoisier
Journal: JAMA Oncology (2023)

Xerostomia is a major toxic effect associated with intensity-modulated radiotherapy (IMRT) for oropharyngeal cancers.
Lung cancer risk discrimination of prediagnostic proteomics measurements compared with existing prediction tools
Authors: Xiaoshuang Feng, Wendy Yi-Ying Wu, Justina Ucheojor Onwuka, Zahra Haider, Karine Alcala, Karl Smith-Byrne, Hana Zahed, Florence Guida, Renwei Wang, Julie K Bassett, Victoria Stevens, Ying Wang, Stephanie Weinstein, Neal D Freedman, Chu Chen, Lesley Tinker, Therese Haugdahl Nøst, Woon-Puay Koh, David Muller, Sandra M Colorado-Yohar, Rosario Tumino, Rayjean J Hung, Christopher I Amos, Xihong Lin, Xuehong Zhang, Alan A Arslan, Maria-Jose Sánchez, Elin Pettersen Sørgjerd, Gianluca Severi, Kristian Hveem, Paul Brennan, Arnulf Langhammer, Roger L Milne, Jian-Min Yuan, Beatrice Melin, Mikael Johansson, Hilary A Robbins, Mattias Johansson
Journal: JNCI Journal of the National Cancer Institute (2023)

We sought to develop a proteomics-based risk model for lung cancer and evaluate its risk-discriminatory performance in comparison with a smoking-based risk model (PLCOm2012) and a commercially available autoantibody biomarker test.